Understanding Immune System Hotspots in Sjögren's Syndrome

Image credit: https://openai.com/index/dall-e/

Scientists have been working hard to understand tertiary lymphoid structures (TLS), which are essentially mini-immune system hubs that can develop in tissues outside of the usual areas like lymph nodes. These structures are particularly relevant in autoimmune conditions such as Sjögren's syndrome (SjS), where they play a significant role in ongoing inflammation and other complications. In SjS, these TLS can lead to overactive B cells, the production of autoantibodies (antibodies that mistakenly target the body's own tissues), and an increased risk of B-cell lymphoma.

This new research takes a deep look into the cells and spatial organization of these TLS within the salivary glands of individuals with Sjögren's syndrome. The scientists also compare these findings to patients with sicca syndrome, which is characterized by dryness, but without the specific antibodies and B cell hyperactivity seen in SjS. The study uses advanced techniques to analyze individual cells and their precise location within the tissue, giving a detailed picture of how these structures are formed and function.

Key Discoveries

• Fibroblasts as Key Players: The research confirms that specific types of fibroblasts are essential for the formation and maintenance of TLS. Fibroblasts are cells that provide structural support to tissues. A particular type of fibroblast called an immuno-fibroblast is crucial. These immuno-fibroblasts express markers such as CD34, CCL19, TNFSF13B, ICAM1, VCAM1, CD82 and CXCL9, and possess similar characteristics to those found in normal lymphoid organs. They help with the movement and survival of immune cells within the TLS.

• Immuno-fibroblast Development: The study suggests these immuno-fibroblasts might originate from a precursor cell, identified by the markers ACKR3 and CD55. It appears that this precursor cell population decreases as the TLS become more organized, while the immuno-fibroblast cell population increases, suggesting a process of differentiation. This shows how the cells change as the TLS develops.

• Pericytes' Role: Another important cell type discovered is a subset of pericytes or mural cells, which are usually located around blood vessels. These pericytes are identified by the markers CCL21, CCL19, and tenascin C (TNC). They produce T-cell attracting chemokines and act independently from the signaling pathways used by immuno-fibroblasts. Instead, these pericytes respond to inflammatory signals, such as TNFα and IFNγ, suggesting a different mechanism for their involvement. These pericytes are present from early stages of TLS development, potentially recruiting the initial immune cells.

• Sjögren's vs. Sicca Syndrome: The research highlights key differences between Sjögren's and Sicca syndromes. Although the CCL21/CCL19 expressing pericytes are present in both conditions (with lower CCL19 expression in Sicca), the immuno-fibroblast cluster is not found in Sicca syndrome. This suggests that the absence of these specific fibroblasts might be why TLS do not form in Sicca syndrome. Furthermore, specific T and B cell populations were identified in Sjögren's, but not in Sicca.

• Fibroblast Activation: Experiments demonstrate that inflammatory signals from immune cells can activate fibroblasts. This activation causes them to produce molecules such as CD40 and VCAM-1. Furthermore, immuno-fibroblasts can influence T cells, driving them towards a more inflammatory state.

• TLS Development: The researchers used microdissection to study TLS at various stages of development. They observed that as TLS develop, the number of immuno-fibroblasts increases, while the potential precursor cells decrease. Fully developed TLS with germinal centres (GC) showed different gene and protein profiles compared to normal lymphoid tissue, with a greater enrichment in inflammatory markers. This difference might explain the increased risk of lymphoma in Sjögren's syndrome.

• Spatial Organization: Using advanced imaging techniques, the study mapped the location of different cell types within the developing TLS, identifying distinct areas rich in B cells, T cells, and immuno-fibroblasts. The researchers identified 5 different "neighborhoods" with distinct cellular make up within the TLS.

Implications of the Research

This research offers a comprehensive map of the cellular and molecular processes involved in TLS formation in Sjögren's syndrome. Understanding how these structures develop could open new doors for therapeutic interventions designed to manipulate or prevent TLS formation in Sjögren's and other diseases. Identifying the differences between Sjögren's and Sicca syndromes could also improve diagnosis and treatment strategies. The unique inflammatory nature of TLS compared to normal lymphoid structures highlights the need to control inflammation within these structures to prevent complications like lymphoma.

In conclusion, this study highlights the intricate interaction between different cell types, particularly fibroblasts and pericytes, in the formation of TLS. It also suggests potential therapeutic targets for autoimmune diseases, such as Sjögren's syndrome. By identifying unique cellular markers, the study advances understanding of the cellular basis of Sjögren’s syndrome and offers paths to treatments that could improve the lives of patients. The discovery of a progenitor cell for immuno-fibroblasts and a unique subset of pericytes, provides new understanding of the formation of these structures. Furthermore, the finding that TLS are more inflammatory than normal lymphoid structures, suggests that current approaches to immune suppression may not be adequate to treat patients with Sjögren’s syndrome.
 
Journal information: Molecular and spatial analysis of tertiary lymphoid structures in Sjogren’s syndrome. Nature Communications (2024).  https://doi.org/10.1038/s41467-024-54686-0
Additional information: https://www.nature.com/ncomms/